1772

Guidance for Industry and Food
and Drug Administration Staff
Factors to Consider When Making

Benefit-Risk Determinations in
Medical Device Premarket
Approval and De Novo
Classifications
Document issued on August 24, 2016.
The draft of this document was issued on August 15, 2011.
As of October 23, 2016, this document supersedes

Factors to Consider When Making Benefit-Risk
Determinations in Medical Device Premarket Approvals
and De Novo Classifications dated March 28, 2012.
For questions about this document concerning devices regulated by CDRH, contact the
Office of the Center Director at 301-796-5900. For questions about this document concerning
devices regulated by CBER, contact the Office of Communication, Outreach and
Development (OCOD) by calling 800-835-4709 or 301-827-1800.
U.S. Department of Health and Human Services

Food and Drug Administration
Center for Devices and Radiological Health
Center for Biologics Evaluation and Research
1
Contains Nonbinding Recommendations
Preface
Public Comment
You may submit electronic comments and suggestions at any time for Agency consideration to
http://www.regulations.gov . Submit written comments to the Division of Dockets Management,
Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD
20852. Identify all comments with the docket number FDA-2011-D-0577. Comments may not be
acted upon by the Agency until the document is next revised or updated.
Additional Copies
CDRH
Additional copies are available from the Internet. You may also send an e-mail request to
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document
number 1772 to identify the guidance you are requesting.
CBER
Additional copies are available from the Center for Biologics Evaluation and Research (CBER)
by written request, Office of Communication, Outreach, and Development (OCOD), 10903 New
Hampshire Ave., WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-4709
or 240-402-8010, by email, ocod@fda.hhs.gov, or from the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm.
2
Table of Contents
1. Introduction .......................................................................................................................................................4
2. Scope .................................................................................................................................................................4
3. Background .......................................................................................................................................................5
3.1 The Statutory Standard for Safety and Effectiveness...................................................................................5
3.2 Types of Scientific Evidence .......................................................................................................................6
3.3 Benefit-Risk Determinations .......................................................................................................................7
4. Factors FDA Considers in Making Benefit-Risk Determinations......................................................................8

4.1 Assessment of the Benefits of Devices .....................................................................................................8
4.2 Assessment of the Risks of Devices.............................................................................................................9
4.3 Additional Factors in the Assessment of the Probable Benefits and Risks of Devices ..............................11
5. Examples of Benefit-Risk Determinations.......................................................................................................14

5.1 Hypothetical Examples ..............................................................................................................................14
5.2 Examples Based on Actual FDA Benefit-Risk Determinations .................................................................21
Appendix A ..........................................................................................................................................................23
Intersection of this Guidance with ISO 14971 ..................................................................................................23
Appendix B...........................................................................................................................................................24
Worksheet for Benefit-Risk Determinations.....................................................................................................24
Appendix C...........................................................................................................................................................31
Worksheets for Hypothetical Examples............................................................................................................31
Worksheet for Hypothetical Example 1 ............................................................................................32
3
Guidance for Industry and

Food and Drug Administration Staff
Factors to Consider When Making

Benefit-Risk Determinations in Medical
Device Premarket Approval and De Novo
Classifications
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on
FDA or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA
staff or Office responsible for this guidance as listed on the title page.
1. Introduction
FDA has developed this guidance document to provide greater clarity for FDA reviewers
and industry regarding the principal factors FDA considers when making benefit-risk
determinations during the premarket review process for certain medical devices. FDA
believes that the uniform application of the factors listed in this guidance document will
improve the predictability, consistency, and transparency of the premarket review
process.
FDA's guidance documents, including this one, do not establish legally enforceable
responsibilities. Instead, guidance documents describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless specific regulatory or
statutory requirements are cited. The use of the word should in Agency guidance
documents means that something is suggested or recommended, but not required.
2. Scope
This guidance document explains the principal factors that FDA considers when making
benefit-risk determinations in the premarket review of certain medical devices. The
processes discussed in this guidance are applicable to devices subject to premarket
4
approval (PMA) applications or de novo classification requests. This guidance applies to

both diagnostic and therapeutic devices. The concepts discussed in this guidance are
applicable to the medical device development process from design to market. As such,
the benefit-risk factors set out herein should be considered during the design, non-clinical
testing, pre-Investigational Device Exemption (IDE), and IDE phases as well as in
assembling and assessing PMA applications or de novo requests. Although guidance is
not binding, the concepts and factors described herein generally explain how benefit-risk
determinations are made by FDA during the premarket review process. The intersection
of this Guidance with ISO 14971 is discussed in AppendixA.
3. Background
3.1 The Statutory Standard for Safety and Effectiveness
Under section 513(a) of the Federal Food, Drug & Cosmetic Act (the FD&C Act), FDA
determines whether PMA applications provide a reasonable assurance of safety and
effectiveness by weighing any probable benefit to health from the use of the device
against any probable risk of injury or illness from such use, among other relevant
factors.1 To aid in this process, PMA applicants submit valid scientific evidence,
including one or more clinical investigations where appropriate, which FDA reviews to
determine whether the device will have the effect it purports or is represented to have
under the conditions of use prescribed, recommended, or suggested in the labeling of the
device.2 FDA staff review the data submitted as part of the PMA application and
determine based on a number of factors if the data support the claims made by the
sponsor concerning clinically significant results from the device, i.e., intended use and
1
In addition to section 513(a), the criteria for establishing safety and effectiveness of a device are set forth
in 21 CFR 860.7. Subsection (b)(1) notes, In determining the safety and effectiveness of a device the
Commissioner and the classification panels will consider the following, among other relevant factors The
probable benefit to health from the use of the device weighed against any probable injury or illness from
such use. (21 CFR 860.7(b)).
To make this determination, the agency relies upon only valid scientific evidence. (21 CFR 860.7(c)(1)).
Valid scientific evidence is defined as evidence from well-controlled investigations, partially controlled
studies, studies and objective trials without matched controls, well-documented case histories conducted by
qualified experts, and reports of significant human experience with a marketed device, from which it can
fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and
effectiveness of a device under its conditions of use. (21 CFR 860.7(c)(2)).
A reasonable assurance of safety occurs when it can be determined, based upon valid scientific evidence,
that the probable benefits outweigh any probable risks, and can be demonstrated by establishing the
absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses
and conditions of use. (21 CFR 860.7(d)(1)).
Similarly, a reasonable assurance of effectiveness occurs when it can be determined, based upon valid
scientific evidence the use of the device for its intended uses will provide clinically significant results.
(21 CFR 860.7(e)(1)). The evidence of which is demonstrated principally through well-controlled
investigations (see 21 CFR 860.7(e)(2)), as defined in 21 CFR 860.7(f).
2
Section 513(a)(3)(A) of the FD&C Act.
5
indications for use, and if the data analysis demonstrates that the probable3 benefits of the
device outweigh its probable risks. A balanced consideration of probable benefits and
probable risks is an essential part of FDAs determination that there are reasonable
assurances of safety and effectiveness.4 Other considerations include that the device is
being manufactured in accordance with FDAs quality system requirements.5
Similarly, in accordance with section 513(f)(2) of the FD&C Act, sponsors of devices that
have been determined to be not substantially equivalent (NSE) through the 510(k)
program may be eligible to submit a de novo request requesting FDA to make a risk-
based classification determination for the device under section 513(a)(1) of the FD&C
Act.6 Because devices classified under this pathway (de novo devices) are low to
moderate risk devices, they may not need to confer as substantial a benefit to patients7 in
order to have a favorable benefit-risk profile. Devices granted marketing authority under
de novo requests should be sufficiently understood to explain all the risks and benefits of
the device such that all risks can be appropriately mitigated through the application of
general and/or special controls to provide reasonable assurance of safety and
effectiveness. Further, devices classified under de novo requests may serve as predicates
for future devices which can be appropriately regulated through the 510(k) program;
therefore, FDA carefully considers the benefit-risk profile of these devices in the
determination that there is reasonable assurance of safety and effectiveness.
3.2 Types of Scientific Evidence
Medical devices can be evaluated using clinical and non-clinical testing methods. Clinical
testing methods for medical devices can include, when appropriate, randomized clinical
trials in the appropriate target population, well-controlled investigations, partially
controlled studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, reports of significant human
experience, and testing on clinically derived human specimens (DNA, tissue, organ and
cadaver studies).8 Non-clinical testing methods can encompass an array of methods
including performance testing for product safety/reliability/characterization, human
factors and usability engineering testing under simulated conditions of use, animal and
3
In general, probable and probability in this guidance have the same connotation as in 21 CFR
860.7(b)(3), i.e. they refer to the likelihood of the patient experiencing a benefit or risk. Hypothesis testing,
formal concepts of probability and predictive probability, likelihood, etc., typically are critical elements in
the assessment of probable benefit and risk. FDA does not intend for the use of the term probable
benefit in this guidance to refer to the regulatory context for Humanitarian Device Exemptions (HDE)
under section 520(m) of the FD&C Act, and FDAs implementing HDE regulations.
4
Equally important is FDAs determination of effectiveness. See footnote 1.
5
See 21 CFR Part 820.
6
See Draft Guidance for Industry and Food and Drug Administration Staff - De Novo Classification
Process (Evaluation of Automatic Class III Designation).
7
In general, for the purposes of this guidance, the use of the term patient refers to an individual who is
under medical care or treatment and is not a subject, and the use of the term subject refers to an individual
who participates in a clinical investigation.
8
See 21 CFR 860.7.
6
cell-based studies, and computer simulations. These tests characterize mechanical,

electrical and chemical properties of the devices including but not limited to wear, tensile
strength, compression, flow rate, burst pressure, biocompatibility, toxicity,
electromagnetic compatibility (EMC), sterility, stability/shelf life data, software
validation, and testing of synthetic samples, including cell lines. The information
obtained from any clinical and/or non-clinical testing is taken into account during the
premarket review process and FDAs benefit-risk determination.
Although a great deal of emphasis is placed on the importance of clinical data in

demonstrating the safety and effectiveness of a medical device, non-clinical data also can
be critical to understanding a devices safety and effectiveness. Medical devices often
have attributes that cannot be tested using clinical methods alone and that play a major
role in the safety or effectiveness of the device.
Both clinical and non-clinical testing methods may be used to assess the probability or
severity of a given risk, and/or the success of risk mitigation. For example, in the case of
some implants, the most robust long-term evidence comes from engineering tests that are
able to challenge the device under worst-case conditions, test the device to failure, and
simulate many years of use. In contrast, clinical studies are usually limited in duration of
follow-up, and, as a result, may be less informative with respect to the long-term
performance of the device. In this case, the results of engineering testing may
significantly influence FDA's benefit-risk determination independent of the clinical
findings.
Both clinical and non-clinical data can play a role in FDAs benefit-risk determinations,
and the factors discussed in this guidance are informed by both types of data.
FDA relies on valid scientific evidence in making risk and benefit determinations,
including the critical issue of identifying probable risks and probable benefits in the
first place. In general, a probable risk and a probable benefit do not include
theoretical risks and benefits, and instead are ones whose existence and characteristics are
supported by valid scientific evidence. Generally, isolated case reports, random
experience, reports lacking sufficient details to permit scientific evaluation, and
unsubstantiated opinions are not regarded as valid scientific evidence to show safety or
effectiveness. However, such information may be considered in identifying a device that
has questionable safety and effectiveness.9
3.3 Benefit-Risk Determinations
The factors FDA considers as part of the benefit-risk determination are explained in detail
below. We also give examples of how the factors interrelate and how they may affect
FDAs decisions. By providing greater clarity about FDAs decision-making process, we
9
21 CFR 860.7(c)(2).
7
hope to improve the predictability, consistency, and transparency of the review process
for applicable devices.
We have also included a worksheet that reviewers will use in making benefit-risk
determinations as part of the premarket review process. The worksheet is attached as
AppendixB to this guidance, and examples of how reviewers might use the worksheet are
attached as AppendixC. By documenting reviewers thought processes as part of the
administrative record and, in certain cases, the publicly available summary of our
decision,10 sponsors will have a better idea of the basis for FDAs favorable decisions and
gain a greater understanding of what factors were considered as part of an approval or a
down-classification decision through the de novo process. However, because the
weighting of the factors for a type of device may change over time such as a device no
longer being a first-of-a-kind or the only available treatment as new therapies are
approved the benefit-risk determination for a specific device at one point in time may
no longer represent the proper weighting of the factors for the same or similar type of
device in the future.
4. Factors FDA Considers in Making Benefit-Risk

Determinations
The factors described below are considered within the intended use of the device,
including the target population. These sections are not intended to provide device-
specific data requirements for the assessment of the factors or methods by which
inferences will be drawn from the data.
4.1 Assessment of the Benefits of Devices
Extent of the probable benefit(s): FDA assesses information provided in a PMA

application or de novo request concerning the extent of the probable benefit(s) by taking
into account the following factors individually and in the aggregate:
- The type of benefit(s) examples include but are not limited to the devices
impact on clinical management, patient health, and patient satisfaction in the
target population, such as significantly improving patient management and quality
of life, reducing the probability of death, aiding improvement of patient function,
reducing the probability of loss of function, and providing relief from symptoms.
These endpoints denoting clinical benefit are usually measured directly, but in
some cases may be demonstrated by use of validated surrogate endpoints. For
diagnostics, a benefit may be assessed according to the public health impact of a
particular device, due to its ability to identify a specific disease and therefore
prevent its spread, predict future disease onset, provide earlier diagnosis of
diseases, or identify patients more likely to respond to a given therapy.
10
See http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma/cfm.
8
- The magnitude of the benefit(s) we often assess benefit along a scale or

according to specific endpoints or criteria (types of benefits), or by evaluating
whether a pre-identified health threshold was achieved. The change in
participants condition or clinical management as measured on that scale, or as
determined by an improvement or worsening of the endpoint, is what allows us to
determine the magnitude of the benefit in participants. Variation in the
magnitude of the benefit across a population may also be considered.
- The probability of the patient experiencing one or more benefit(s) based on

the data provided, it is sometimes possible to predict which patients may
experience a benefit, whereas other times this cannot be well predicted. The data
may show that a benefit may be experienced only by a small portion of patients in
the target population, or, on the other hand, that a benefit may occur frequently in
patients throughout the target population. It is also possible that the data will
show that different patient subgroups are likely to experience different benefits or
different levels of the same benefit. If the subgroups can be identified, the device
may be indicated for those subgroups. In some cases, however, the subgroups
may not be identifiable. In addition, we consider magnitude and probability
together when weighing benefits against risks. That is, a large benefit experienced
by a small proportion of participants may raise different considerations than does a
small benefit experienced by a large proportion of participants. For example, a
large benefit, even if experienced by a small population, may be significant enough
to outweigh risks, whereas a small benefit may not, unless experienced by a large
population of participants.
- The duration of effect(s) (i.e., how long the benefit can be expected to last for the
patient) some treatments are curative, whereas, some may need to be repeated
frequently over the patients lifetime. To the extent that it is known, the duration
of a treatments effect may directly influence how its benefit is defined.
Treatments that must be repeated over time may introduce greater risk, or the
benefit experienced may diminish each time the treatment is repeated.
4.2 Assessment of the Risks of Devices

Extent of the probable risk(s)/harm(s): FDA assesses the extent of the probable
risk(s)/harm(s) by taking into account the following factors individually and in the
aggregate:
- Severity, types, number and rates11 of harmful events associated with the use
of the device:12
11
For purposes of this guidance, rates means the number of harmful events per patient or number of
harmful events per unit of time.
12
We have listed each type of harm individually for the purpose of clarifying which of the more commonly
recognized harms FDA would consider in benefit-risk assessments. In making benefit-risk assessments,
9
o Device-related serious adverse events those events that may have been
or were attributed to the use of the device and produce an injury or illness
that is life-threatening, results in permanent impairment or damage to the
body, or requires medical or surgical intervention to prevent permanent
harm to the body.13
o Device-related non-serious adverse events those events that may have

been or were attributed to the use of the device and that do not meet the
criteria for classification as a device-related serious adverse event.
o Procedure-related complications harms to the patient that would not be
included under serious or non-serious adverse events, and that do not
directly result from use of the device. For example, anesthetic-related
complications associated with the implantation of a device. Similarly,
FDA would factor risks associated with the collection of human biological
materials into the benefit-risk determination.14
- Probability of a harmful event the proportion of the intended population that

would be expected to experience a harmful event. FDA would factor whether an
event occurs once or repeatedly into the measurement of probability.
- Duration of harmful events (i.e., how long the adverse consequences last)
some devices can cause temporary, minor harm; some devices can cause repeated
but reversible harm; and other devices can cause permanent, debilitating injury.
FDA would consider the severity of the harm along with its duration.
- Risk from false-positive or false-negative results for diagnostics if a

diagnostic device gives a false-positive result, the patient might, for example,
receive an unnecessary treatment and incur all the risks that accompany that
treatment, or might be incorrectly diagnosed with a serious disease. If a
diagnostic device gives a false-negative result, the patient might not receive an
effective treatment (thereby missing out on the benefits that treatment would
confer), or might not be diagnosed with the correct disease or condition. The risks
associated with false-positives and false-negatives can be multifold, but are
considered by FDA in light of probable risks.
We also consider the number of different types of harmful events that may result from
using the device and the severity of their aggregate effect. When multiple harmful
events occur at once, they have a greater aggregate effect. For example, there may be a
harmful event that is considered minor when it occurs on its own, but, when it
FDA does not consider each type of harm individually, but rather looks at the totality of the harmful events
associated with the device.
13
See 21 CFR 803.3.
14
These considerations affect the risk profile of in vitro diagnostic devices when the biological material is
collected via an invasive procedure for the purpose of performing the diagnostic test.
10
occurs along with other harmful events, the aggregate effect on the patient can be
substantial.
4.3 Additional Factors in the Assessment of the Probable Benefits and

Risks of Devices
Uncertainty there is never 100% certainty when determining reasonable assurance of

safety and effectiveness of a device. However, the degree of certainty of the benefits and
risks of a device is a factor we consider when making benefit-risk determinations.
Factors such as poor design or poor conduct of clinical trials, or inadequate analysis of
data, can render the outcomes of the study unreliable. Additionally, for certain device
types, it is sometimes difficult to distinguish between a real effect and a placebo effect in
the absence of a trial design that is capable of masking investigators and participants.
Furthermore, the repeatability of the study results, the validation of the analytical
approach, and the results of other similar studies and whether the study is the first of its
kind or a standalone investigation can all influence the level of certainty. In addition, the
generalizability of the trial results to the intended treatment and user population is
important. For example, if the device requires in-depth user training or specialization, the
results of the clinical study may not be generalizable to a wider physician population.
Likewise, if the device is intended to diagnose a disease in a subpopulation, it may not be
useful in the general population. In general, it is important to consider the degree to
which a clinical trial population is representative of the intended marketing or target
population.
Patient-centric assessments and patient-reported outcomes (PROs) We

recognize that patient-centric metrics such as validated health-related quality of life
measures and other Patient-Reported Outcomes (PROs) (e.g., scales or scores
indicating patients experience of pain or function) can be helpful for patients and
health care practitioners when discussing treatment options and decisions, and may
be used to demonstrate benefit for purposes of product approval. These types of
metrics allow the physician to better quantify the impact of the device on the
patients well-being and help the patient make a more informed decision.
Characterization of the disease the treated or diagnosed condition, its clinical

manifestation, how it affects the patients who have it, how and whether a diagnosed
condition is treated, and the conditions natural history and progression (i.e., does it get
progressively better or worse for the patient and at what expected rate) are all important
factors that FDA considers when characterizing disease and determining benefits and
risks.
Patient perspectives if the risks are identifiable and definable, risk tolerance will vary
among patients, and this will affect individual patient decisions as to whether the risks are
acceptable in exchange for a probable benefit. When making a benefit-risk determination
at the time of approval or de novo classification, FDA recognizes that patient perspectives
on benefits and risks may reveal reasonable patients who are willing to tolerate a very
high level of risk to achieve a probable benefit, especially if that benefit results in an
11
improvement in quality of life. Rather than one-sided evaluations, patient preference
assessments should take into account both the patients willingness and unwillingness to
use a device or tolerate risk in exchange for probable benefit, and/or evaluate how patients
view trade-offs between benefits and risks of various treatment options.
Patient preference studies can provide insight on how patients value benefits in
comparison to risk. Patient preference information is defined as the qualitative or
quantitative assessment of the relative desirability or acceptability to patients of specified
alternatives or choices among outcomes or other attributes that differ among alternative
health interventions.15 FDA may also consider the preferences of care-partners (e.g.,
parents) and healthcare professionals to the extent they are relevant in the benefit-risk
assessments for a particular device subject to review in a PMA, HDE application, or de
novo request.
For more information regarding patient preference studies, consult FDA Guidance:
Patient Preference Information Voluntary Submission, Review in PMAs, HDE
Applications, and De Novo Requests, and Inclusion in Decision Summaries and Device
Labeling.
How data concerning patient risk tolerance and other patient-centered metrics are developed
will vary depending on a number of factors, including the nature of the disease or condition
and the availability of existing treatments, as well as the risks and benefits they present.
FDA encourages any sponsor that is considering developing such data to have early
interaction with the appropriate FDA review division.
When assessing such data in a PMA application or de novo request, FDA realizes that
some patients are willing to take on a very high risk to achieve a small benefit, whereas
others are more risk averse. Therefore, FDA would consider evidence relating to
patients perspective of what constitutes a meaningful benefit when determining if the
device is effective, as some set of patients may value a benefit more than others. It
should also be noted that if, for a certain device, the probable risks outweigh the probable
benefits for all reasonable patients, FDA would consider use of such a device to be
inherently unreasonable.16
Patient preference information may demonstrate that most, if not all, of the patient
population with a specific disease or condition consider the benefit-risk tradeoffs
acceptable. Different factors can influence patient perspective on benefits and risks,
including:
- Severity of disease or condition patients suffering from very severe diseases

(i.e., those that are life-threatening) may tolerate more risk for devices used in
treatment. For diagnostic devices, individuals might be more averse to the risk of a
false negative result concerning a severe disease.
15
Adapted from: Medical Device Innovation Consortium. A framework for incorporating information on
patient preferences regarding benefit and risk into regulatory assessments of new medical technology. 2015.
(http://mdic.org/wp-content/uploads/2015/05/MDIC_PCBR_Framework_Proof5_Web.pdf).
16
For the purposes of this guidance unreasonable risk" refers to a risk that no set of reasonable patients
would be willing to endure to achieve a probable benefit.
12
- Disease chronicity some patients with chronic diseases who have adapted to their
illness and minimized its interference with their daily lives may tolerate less risk
and require risky devices to deliver a greater treatment benefit, whereas other
patients who have suffered from a debilitating chronic illness over a long period of
time may tolerate higher risk to gain less benefit.
- Availability of alternative treatment/diagnostic options (also see below) if

there are no other treatment/diagnostic options available, patients may tolerate
more risk for even a small amount of benefit.
Availability of alternative treatments or diagnostics when making benefit-risk

determinations, FDA considers whether other treatments or diagnostics, including non-
device therapies, have been approved or cleared for the intended condition and patient
population. When considering other therapies, FDA takes into account how effective
they are; what known risks they pose; how they are used in current medical practice; their
benefit-risk profiles; and how well available alternatives address the needs of patients and
providers. For a device with a known benefit and a probability of high risk that treats a
condition for which no alternative treatments are available, FDA would consider the risk
to the patient of having no treatment if a device were not approved. For example, if a
new device has a very small significant benefit and there is significant uncertainty about
that benefit, we may still approve the product if there are no available alternative
treatments and the probable benefits outweigh the probable risks.
13
14
Risk mitigation the use of mitigations, when appropriate, can minimize the probability
of a harmful event occurring and improve the benefit-risk profile. The most common form
of risk mitigation is to include appropriate information within labeling (e.g., warnings,
precautions, etc.), or to restrict the indication to a more limited use. Some harms can be
mitigated through other forms of risk communication, including training and patient
labeling. For in vitro diagnostics, risks may be mitigated by the use of complementary
diagnostic tests.
Postmarket data the use of devices in a real world setting can provide a greater
understanding of their risks and benefits. FDA may consider the collection of postmarket
data as a way to clarify the magnitude and effect of mitigations or as a way to develop
additional information regarding benefits or risks for certain device types or in specific
patient populations when making a benefit-risk determination. FDA has the authority to
require post-approval studies for PMA devices and postmarket surveillance for PMA and
de novo devices.17 In addition, pursuant to section 513(a)(3)(C) of the FD&C Act, in
certain cases, such as if a device is likely to be denied approval due to uncertainty about its
effectiveness, FDA will consider whether postmarket data collection or other conditions
might be structured so as to permit approval subject to those conditions.
These types of studies or other data that come to light after the device is used in the real-
world setting may alter the benefit-risk profiles of certain devices, especially if new risks
are identified, or if the information can be used to confirm that certain risks have been
mitigated, to identify which patients are most likely to suffer adverse events, or to identify
more specifically how different groups of patients will respond.
Novel technology addressing unmet medical need in assessing benefit and risk, FDA
considers whether a device represents or incorporates breakthrough technologies and
addresses an unmet medical need. A device may address unmet medical need by providing
a clinically meaningful advantage over existing technologies, providing a greater clinically
meaningful benefit than existing therapy, posing less risk than existing therapy, or
providing a treatment or means of diagnosis where no alternative is available.
17
21 CFR 814.82 states that FDA may impose postapproval requirements in a PMA approval order or by
regulation at the time of approval of the PMA or by regulation subsequent to approval. In addition, under
section 522 of the FD&C Act, and FDAs implementing regulations at 21 CFR Part 822, FDA may order
postmarket surveillance for certain Class II or Class III devices.
15
It is not unusual for novel devices that address an unmet medical need to have relatively
small probable benefits, and FDA may determine the novel device to be reasonably safe
and effective even though the applicant demonstrates a relatively small probable benefit.
In addition, the development of innovative technology may provide additional future
benefits to patients. With subsequent iterations of the device its benefit-risk profile may
change (e.g., the benefits may increase or the risks may be reduced), the expected level of
safety and effectiveness may change, and later versions may offer significant advantages
over the initial device. In these circumstances, in order to facilitate patient access to new
devices important for public health and to encourage innovation, we may tolerate greater
uncertainty in an assessment of benefit or risk than for most established technologies,
particularly when providers and patients have limited alternatives available.
5. Examples of Benefit-Risk Determinations

The examples below are hypothetical or simplified and are only offered for illustrative
purposes. The decisions described in these examples are not predictive of future FDA
decisions, rather they are hypothetical outcomes and are only intended to demonstrate
how FDA considers the factors described in this guidance when making benefit-risk
determinations. Similar scenarios or devices may result in different approval outcomes
depending on the individual performance characteristics of a particular device and the
population for which it is indicated.
A description of how FDA would consider these examples in the context of the reviewer
worksheet is included in AppendixC.
5.1 Hypothetical Examples
Example 1
An implantable device is developed to treat a severe, chronic condition for patients who
have failed all other treatment options.
The device is studied in a pivotal clinical trial with a design where all participants are
implanted with the device, but the device is only turned on in half of them. After
completion of the trial, inactive devices can be turned on. The primary endpoint for the
trial is the magnitude of the benefit, i.e., the trial is designed to measure how well the
device reduces the subjects symptoms as compared to the current standard of care.
The results of the pivotal clinical trial revealed the following:
Benefits: Based on the clinical study, it is inferred that the probability that a patient will
experience a substantial benefit when the device is implanted is 75%. The trial was
considered to have met its primary endpoint. As a general matter, patients with this
disease who are able to maintain good mobility tend to have a longer life expectancy.
16
However, the duration of the benefit cannot be determined because the subjects in the
study were only followed for one year.
Risks: The study showed that there is a very low probability of occurrence (less than
3%) of harmful events after device implantation. However, all implanted devices that
require a surgical procedure carry with them their own set of risks. In this case it is
known from the literature that the implantation of this device is not routine and there is a
1% chance of death from surgery. In addition, permanent implants pose additional risks,
namely, they typically remain with the patient for life and may be difficult to remove.
Even in cases where the device is deactivated, it remains implanted and a risk of device
fracture, mechanical failure, or an adverse biological response to the device remains (the
probability is less than 3%).
Additional Factors:
Uncertainty: It is difficult to discern the mechanism of action by which subjects
symptoms improved and whether the surgery may have contributed to such improvement.
Because the trial ended after one year, it is difficult to determine the duration of the
benefit beyond one year. There is only a 75% chance that a patient will experience total
success when implanted with the device.
Patient Perspectives: The sponsor provided data showing that most patients are willing
to take the risk of having the device implanted even for a 75% probability of benefit
because the alternative treatment options do not work for them and their symptoms are
severe.
Risk Mitigation: The surgery to implant and explant (if necessary) the device is risky, but
the risks can be mitigated by requiring the device to be implanted by a specially trained
surgeon.
Approval/Non-Approval Considerations: The probability that a patient will experience

a benefit is relatively high (approximately 75%, if the clinical trial results hold for the
intended use population). In this particular case, FDA does not have the option to limit
the use of the device to only those patients who are most likely to experience a benefit
because the covariates that determine the subgroup of patients who would definitely
experience the benefit are unknown. In addition, this type of permanently implantable
device poses significant risks and there is some remaining uncertainty associated with the
trial results. However, for those patients in the target population who will experience a
benefit, symptom relief and improvement in quality of life is impressive and some
patients have expressed a willingness to tolerate the risks as a trade-off for obtaining such
benefits. In addition, the risks, although substantial, could be somewhat mitigated
through limiting the device use to clinicians with specialized training. Finally, the device
treats a severe and chronic disease for which there are few, if any, alternative treatments.
Therefore, FDA is likely to approve the device.
17
Example 2
A novel device that replaces a patients memory is developed to treat Alzheimers

disease, dementia, and other memory disorders. The device is designed to be
permanently implanted and the patient must undergo a brain resection for the device to
work properly. The device functions by downloading all of a patients memories onto a
computer chip. Once the device is implanted, any residual memory the patient retained is
no longer accessible to the patient.
Benefits: A clinical trial of the device showed significant improvement in subjects who
were in the early stages of dementia and minimal improvement in subjects who were in
more advanced stages. Subjects who received implanted devices when the majority of
their memory was intact experienced the greatest benefit and their overall quality of life
was enhanced. Since the trial design accounted for two subgroups, subjects at the early
stage of the disease and subjects at advanced stages of the disease, it can be inferred that,
if the device is marketed, the patient population in early stages of the disease is likely to
experience significant improvement, whereas the patient population in advanced stages is
likely to experience only minimal improvement.
Risks: The surgery to implant the device is highly risky and is usually only performed by
specially trained neurosurgeons. Even with these procedural restrictions, it is known
from previous studies and literature that there is an 8% risk of serious adverse events
from the surgery alone. In addition, the clinical study showed that adverse events include
partial paralysis, loss of vision, loss of motor skills, vertigo, and insomnia (predictive
probability of 1%). Non-serious adverse events include temporary personality shifts,
mood swings, and slurred speech (predictive probability shown in the study was 5%).
Additional Factors:
Uncertainty: The number of subjects eligible and willing to enroll in the trial was small,
but the data were robust and the trial was well-designed and conducted. The results of the
trial are generalizable. The study showed that the subjects likely to experience the best
results are the ones at early stages of memory loss.
Patient Perspectives: Because of the serious effect on patients quality of life from
diseases like Alzheimers, other forms of dementia, and other conditions that are
associated with severe memory loss, as well as the progressive nature of Alzheimers,
some patients with these conditions, and their care-partners, often have a very high
tolerance for risk, even a risk of serious adverse events, in exchange for a probable
improvement of the disease symptoms, and for alleviating the burden that they
anticipate they will place on family members during the later stages of the disease.
Other patients, such as those at older ages, may be less willing to tolerate such risks.
Patients who are at more advanced stages of their illness and experiencing more severe
symptoms are less likely to benefit from the device. Furthermore, their tolerance for
risk is difficult to assess due to their advanced disease.
18
Availability of Alternative Treatments or Diagnostics: There are currently no alternative
treatments available.
RiskMitigation: The risks associated with this device are great. The risks associated
with implantation and explantation (if necessary) can be somewhat mitigated by limiting
use to surgeons who have undergone special training, but the risks associated with
personality changes cannot be mitigated or predicted. The risks can also be mitigated by
indicating the device for patients at earlier stages of the disease who are more likely to
benefit, and explaining in the labeling using data from the clinical trial that individuals
experiencing more severe symptoms are less likely to benefit from the device.
NovelTechnologyAddressingUnmetMedicalNeed: There is no other similar technology

available. It is possible that future improvements of the device may allow treatment of
many other conditions that affect cognitive function. Moreover, there are no other
treatments that provide the level of benefit that this device confers on the target
population.
Approval/Non-Approval Considerations: The device will confer a substantial benefit

for a defined and predictable subgroup of patients and a minimal benefit for another
defined and predictable subgroup. Even though the clinical trial was small, the quality of
the data was good and the resulting confidence intervals are narrow. The uncertainty
about results is the usual uncertainty resulting from drawing inferences from a sample in
the study to the population in the market. The risks associated with the device are great
and can be partially mitigated by training the physicians who implant/explant (if
necessary) the device. And, because patients experience the greatest benefit when the
device is implanted earlier, they must expose themselves to the risks for a longer period
of time in order to reap the greatest benefit; therefore, the patients who stand to benefit
most also take on the greatest amount of risk. The sponsor provided data showing that
many patients who suffer from memory disorders are willing to try novel approaches that
have significant risk, in order to preserve their memories and quality of life. The fact that
there are no alternative treatments for this condition is another important consideration.
Even though the device-related risks are high, they are tolerable to some patients because
of the probable benefits they offer, and the progressive nature of the untreated condition.
Furthermore, the risks are known and quantifiable. Therefore, this device, although it
poses substantial risk, may be approvable based on all of these considerations taken in
sum. The decision as to whether or not to implant the device in a particular patient is a
matter of patient preference (perhaps with the involvement of a legally authorized
representative) and medical judgment. After full consideration of the likelihood of, and
timeframe for, progression of disease and the predictability of future impairment without
intervention, FDA is likely to approve the device as long as the labeling prominently
addresses the 8% serious adverse event rate and would provide through conditions of
approval that only highly trained physicians will be able to implant the device.
Example 3
A sponsor claims that its new in vitro diagnostic device (IVD), a serum-based test, can
differentiate patients with BI-RADS 4 mammography results into two groups, namely
patients with a low probability of having cancer for whom the physician may recommend
19
waiting a few months for additional testing, thus avoiding the morbidity associated with a
biopsy, and all other BI-RADS 4 patients for whom a biopsy would be recommended as
currently occurs under standard of care. The proposed intended use is:
The in vitro diagnostic test measures 10 peptide analytes and yields a single
qualitative result. The test is intended for females 40 years or older following
mammography of a breast lesion with a BI-RADS of 4 result to aid physicians in the
decision to recommend a breast biopsy.
Negative test result (Low Risk): immediate biopsy is not recommended, wait a few
months for further tests.
Positive test result (High Risk): immediate biopsy is recommended.
Results from a clinical study in the intended use population (with biopsy results for all
subjects) are:
Biopsy
Malignancy Benign
Test Positive 97 75 172
Negative 3 225 228
100 300 400
Sensitivity=97% (97/100) with 95% two-sided CI: 91.5% to 99.0%
Specificity=75% (225/300) with 95% two-sided CI: 69.8% to 79.6%
Prevalence=25% (100/400)
NPV=98.7% (225/228)
PPV=56.4% (97/172)
Benefits: The main benefit from use of the device is avoiding morbidity associated with
an immediate biopsy for the 57% (228/400) of subjects whose test results indicate a low
probability of having breast cancer.
Risks: Among test-negative subjects, the observed (from immediate biopsy) prevalence
of cancer is 1.3% (3/228 = 1-NPV). The main risk from use of the device is in failing to
biopsy some BI-RADS 4 patients who have biopsy-detectible breast cancer, thus delaying
their diagnosis and treatment. Concerning this risk, the sponsor asserts that a clinically
acceptable prevalence for cancer among non-biopsied BI-RADS 4 subjects is 2% or
lower, because: a) BI-RADS 3 patients are usually counseled not to have an immediate
biopsy (waiting a few months, instead, for further evaluation), and b) the expected
prevalence of breast cancer among BI-RADS 3 patients is 2%. The benefit-risk odds
measurable from the clinical study is 75 (225/3), and the observed risk for non-biopsied
BI-RADS 4 subjects is lower than the expected risk in BI-RADS 3 patients.
Additional Factors:
20
Uncertainty: There are the usual uncertainties tied to statistical confidence intervals
surrounding observed study results.
The benefit-risk odds are not weighted for the clinical impact of avoiding biopsy
morbidity compared to the clinical impact of missing a biopsy-detectible cancer. That is,
the type of benefit is not necessarily commensurate with the type of risk.
There is no assurance that the clinical impact of breast cancers missed among patients
with BI-RADS 4 mammography results is equivalent to the clinical impact of breast
cancers among patients who have BI-RADS 3 results. Hence, there is uncertainty about
the extent of the probable risk(s)/harm(s).
Test-negative BI-RADS 4 patients, who do not undergo biopsy, will receive no

histopathological assessment of benign disease that is present.
Patient Perspectives: Patients tolerance for delayed diagnosis and treatment of breast
cancer typically is low. This needs to be weighed against the value that patients place
on avoiding biopsy-related morbidity.
Availability of alternative treatments or diagnostics: There are no other in vitro

diagnostic devices cleared or approved for the new tests intended use.
Risk mitigation: All women with negative test results will have follow-up visits for
further evaluation and testing.
Approval/Non-Approval Considerations: The kinds and probabilities of benefits and

risks are reasonably defined. A clinical practice reference for acceptable risk is put forth,
to which the tests performance characteristics are aligned. Weighting of the different
kinds of benefits versus risks is not directly addressed, and additional information is
needed to establish whether the trade-offs are acceptable. Given that the benefits are
uncertain and the risk (for a very small number of patients) could be substantial, FDA
might determine that this device is not approvable, but would likely take it to an advisory
panel prior to making a decision.
Example 4 De Novo
A new standalone therapeutic device is developed to provide enhanced stability for more
invasive, higher-risk implanted devices, which could otherwise affix themselves without
support. The device can be used to support a primary device at the time of implantation,
or can be added to an already-implanted device that is malfunctioning.
The device is studied in a prospective, multi-center, single-arm clinical study of over 200
subjects. The primary endpoint for the trial is the magnitude of the benefit, i.e., the trial is
designed to measure how well the device prevents movement and malfunction of the
21
primary device as compared to when it is implanted without the benefit of enhanced

stability.
The results of the pivotal clinical trial revealed the following:
Benefits: Through one year of follow-up, no subject experienced device movement and
only two subjects experienced complications related to the device malfunctioning. This
is a significant improvement over primary device performance when implanted alone and
gives a very high predictive probability that a patient receiving the device will not
experience device movement.
Risks: Through one year of follow-up, there were no fractures of any primary device and
only a handful of malfunctions of the support system, none of which lead to serious
adverse events. The risks of failure of the support system are not high because even if the
support system fails, it is unlikely to lead to an overall failure of the primary device.
Even though all implanted devices that require a surgical procedure carry with them their
own set of risks (e.g., 1% chance of death from surgery), this device is implanted along
with the primary device and consequently does not require an additional surgery to
implant. Or, if it is placed to enhance the performance of a malfunctioning primary
device, it is put in during a surgery that would have otherwise been performed to fix the
malfunctioning primary device. Therefore, the data suggest that adding the support
device during surgery does not appear to increase the risk to the patient.
FDA determined that the support device poses low-to-moderate risk, the risks associated
with its use are well-defined and understood, and the risks can be mitigated by general
and special controls, which would provide reasonable assurance of the safety and
effectiveness of the device. As a consequence, the support device is appropriate for the
de novo pathway.
Additional Factors
Uncertainty: The results of the pivotal clinical trial are limited to one-year of follow-up.
For a permanent, implantable device, longer follow-up times can reduce uncertainty
regarding the long-term safety and effectiveness of the device.
Patient Perspectives: Patients who receive the support device either are already
undergoing a surgery and implantation of the primary device or have had complications
with an existing device that the support device can be used to correct non-surgically. The
results of the pivotal clinical trial indicate that future patients stand to benefit from greater
stability of the primary device as a result of the use of the support device; therefore, most
patients stated they would accept the probable benefits of the device given the probable
risks.
RiskMitigation: For this de novo, FDA established special controls to mitigate the risks
associated with the device and make it appropriate to be classified under Class II. For
20
this device, FDA required demonstration of biocompatibility, sterility, safety and

effectiveness data (including clinical performance data, durability, compatibility,
migration, resistance, corrosion resistance, and delivery and deployment); evaluation of
the MR-compatibility of the device; validation of electromagnetic compatibility of
device; limiting of the device to prescription use; and clear instructions in the labeling
regarding the safe and effective use of the device. Since this device does not require an
additional surgery to be implanted, the surgical risk is not an issue.
NovelTechnologyAddressingUnmetMedicalNeed: This device is the first system that

can access and repair a failed or problematic primary device, providing surgeons with a
minimally-invasive option for re-affixing devices that are not properly positioned or that
have migrated, or those that are at risk of such complications.
Approval/Non-Approval Considerations: The clinical trial results provide assurance of

at least one year of clinical effectiveness of the device. Furthermore, it is important to
consider that the device merely supports and supplements the effectiveness of another
device and its failure would not significantly affect the performance of the primary
device. The device does not pose risks that would rise to the level of a Class III device.
Any safety concerns regarding device failure can be readily addressed through special
controls related to appropriate testing and labeling. Given the device benefits, the ability
to mitigate risks through special controls, and the fact that this device is not life-
supporting or life-sustaining, FDA would be likely to grant a de novo request to classify
this device into Class II.
5.2 Examples Based on Actual FDA Benefit-Risk Determinations
o A device to treat a very rare cancer was tested in a clinical trial that
demonstrated with some uncertainty that the device performed as well as
standard treatment, but not better. However, use of the device did not
have harmful effects as severe as those associated with the standard anti-
cancer treatment, and neither treatment was curative. The cancer was
rapidly progressive and terminal, so the participants had very little time to
live after they were diagnosed. FDA approved this device because it gave
patients access to a treatment that appeared to be equivalent to the standard
of care (with some uncertainty remaining), but that did not cause the same
severity of side effects.
o A permanently implanted cardiovascular monitoring device is intended to
diagnose heart failure. The device is studied and the study shows that its
use reduces the number of days the subject is hospitalized for heart failure
by about three. However, the implantation procedure for the device
requires that the patient be hospitalized for two days. There are similar
devices on the market that provide a similar level of benefit as this device
that do not require an implantation procedure. FDA determined that the
benefit of saving one day of hospitalization does not outweigh the risk of
21
complication from the surgery needed to implant the device and found the
device to be not approvable.
o A permanent birth control device can be placed in a womans reproductive
system through the vagina using a specialized delivery catheter. This
device is a permanent implant and is not intended to be removed.
Explantation of the device would require surgery. Clinical data show that
the device is effective in preventing pregnancy over a two-year period in
women and the safety data show a low incidence of adverse clinical
events. However, study results also show that there are several cases
where the physician had difficulty correctly placing the device. In
addition, the device was noted to be fractured on a follow-up x-ray in a
few study subjects. Given the uncertainty of the long-term impact of the
device, the possibility of device fracture (which was not predicted in any
of the bench and animal testing), and the safety and effectiveness of
alternative therapies, FDA deemed the device to be not approvable for the
intended patient population.
o An implanted device offers a unique design feature in comparison to the
standard of care used to treat similar conditions. While the current
standard of care works very well, it has limitations associated with
hindering the mobility of the patient; in contrast, the novel implanted
device does not affect patient mobility. Based upon the effectiveness data
from the clinical study, the device demonstrates that it has significantly
improved functional outcomes in comparison to the current standard of
care. However, from a safety perspective, the device did present different
adverse events that were different from those of the current standard of
care. The risks can be appropriately mitigated with training of surgical
professionals as well as through proper labeling. In the event the
implant was to fail over time, the clinician could also resort to the current
standard of care. In this situation, despite the different adverse events, the
probable benefits outweighed the risks and FDA approved the device.
22
Appendix A
Intersection of this Guidance with ISO 14971

ISO 14971 provides medical device manufacturers with a framework to systematically
manage the risks to people, property and the environment associated with the use of
medical devices. Specifically, the standard describes a process through which the
medical device manufacturer can identify hazards associated with a medical device,
estimate and evaluate the risks associated with these hazards, control these risks, and
monitor the effectiveness of those controls throughout the products lifecycle.18
Implementing this standard requires the user to make decisions on the acceptability of
individual risks, and overall residual risk for a medical device throughout its lifecycle.
ISO 14971 is an FDA-recognized standard, and assuring conformity with this standard
may help device manufacturers meet the design validation requirements specified in the
Design Controls section of Part 820 of FDAs regulations governing quality systems.19
Part of the premarket review process is an evaluation (direct and/or indirect) of a medical
device manufacturers risk management decisions as they pertain to the requirements to
market a device in the United States.20 The medical device manufacturers risk
management decisions that are directly and/or indirectly evaluated include those
pertaining to risk estimation, risk evaluation, risk acceptability, risk control measures, and
overall residual risk. Good documentation of risk management decisions by
manufacturers helps to streamline the premarket review process for both FDA and
manufacturers. At some point, after the manufacturer has completed its risk management
activities associated with the design phase of product development, the premarket
submission process with FDA is initiated, and the benefit-risk assessment takes on a
different shape, which is the primary focus of this guidance. This guidance discusses the
considerations FDA makes when assessing the benefit-risk profile of a device that has
been designed to deliver the most benefit for the least amount of risk and to provide a
reasonable assurance of safety and effectiveness.
18
ANSI/AAMI/ISO 14971:2007 Medical devices Application of risk management to medical devices, p
xi.
19
Design controls are described in 21 CFR 820.30.
20
Additionally, the manufacturer can engage FDA during the pre-submission stage regarding their proposed
risk management decisions related to clinical study design, biocompatibility testing, preclinical animal
testing, bench testing, etc, and receive preliminary feedback on the adequacy of the decisions probability for
generating information that will establish whether the device meets the requirements to be marketed in the
United States.
23
Appendix B
Worksheet for Benefit-Risk Determinations
24
Factor Questions to Consider Notes

Assessment of Benefits of Devices
- What primary endpoints or surrogate
Type of benefit(s)
endpoints were evaluated?
- What key secondary endpoints or
surrogate endpoints were evaluated?
- What value do patients place on the
benefit?
- For each primary and secondary endpoint

Magnitude of the benefit(s)
or surrogate endpoints evaluated:
o What was the magnitude of each
treatment effect?
- What scale is used to measure the
benefit?
o How did the benefit rank on that
scale?
- Was the study able to predict which
Probability of the patient
patients will experience a benefit?
experiencing one or more
- What is the probability that a patient for
benefit(s)
whom the device is intended will
experience a benefit?
- How did the benefits evaluated vary
across sub-populations? (If the study was
sufficiently powered for subpopulations,
note specific subpopulations, nature of
difference and any known reasons for
these differences.)
- Was there a variation in public health
benefit for different populations?
- Even if the benefit is in a small portion of
the population, do those patients who
would experience the benefit value it?
- Could the duration, if relevant, of each
Duration of effect(s)
treatment effect, including primary and
secondary endpoints be determined? If
so, what was it?
- Is the duration of the benefit achieved of
value to patients?
25

Assessment of Risks of Devices
Severity, types, number and

rates of harmful events (events
and consequences):
Device-related serious - What are the device-related serious

adverse events adverse events for this product?
Device-related non-serious - What are the device-related non-serious

Procedure-related - What other procedure-related

complications complications may a patient be subject
to?
- What percent of the intended patient
Probability of a harmful event
population would expect to experience a
harmful event?
- What is the incidence of each harmful
event in the study population?
- How much uncertainty is in that estimate?
- How does the incidence of harmful events
vary by subpopulation (if applicable)?
- Are patients willing to accept the
probable risk of the harmful event, given
the probable benefits of the device?
Duration of harmful events - How long does the harmful event last?
- Is the harmful event reversible?
- What type of intervention is required to
address the harmful event?
Risk from false-positive or - What are the consequences of a false
false-negative results for positive?
diagnostics - What are the consequences of a false
negative?
- Is this the only means of diagnosing the
problem, or is it part of an overall
diagnostic plan?
26

Additional Factors in Assessing Probable
Benefits and Risks of Devices
Uncertainty:
Quality of the study design - How robust were the data?
Quality of the conduct of the - How was the trial designed,

study conducted and analyzed?
- Are there missing data?
Robustness of the analysis of - Are the study results repeatable?

the study results - Is this study a first of a kind?
- Are there other studies that
achieved similar results?
Generalizability of results - Can the results of the study be applied to

the population generally, or are they
more intended for discrete, specific
groups?
Patient-centric assessments and - Do the device benefits and risks include

patient-reported outcomes (PROs) effects on the health-related quality of
life or other patient-reported outcomes?
Characterization of the - How does the disease affect the

Disease patients that have it?
- Is the condition treatable?
- How does the condition progress?
Patient perspectives:
27
- Benefit and risk considerations - What benefit(s) from this
of patient preference device is (are) of most
information importance to patients?
- What risk(s) from this device is
(are) of most importance to
patients?
- Is there available qualitative or
quantitative patient preference
information (PPI) on the relative
desirability or acceptability to patients
of outcomes or other attributes that
differ among alternative health
interventions?
- Does available PPI show patients are
willing to accept the probable risk(s)
of this device in exchange for the
probable benefit(s)?
- Does available PPI show patient
perspectives on maximum acceptable
risk and minimum acceptable benefit,
for meaningful changes in each risk?
- Does PPI demonstrate that most or
all of the patient population with the
disease or condition consider benefit-
risk tradeoffs acceptable in light of
disease severity, chronicity, or lack of
alternative treatments?
PPI relevance and - Are the risks identifiable and
comprehension definable?
- Do patients understand the type of
risk(s) and the likelihood of the
risk(s)?
benefit(s) and the likelihood of the
benefit(s)?
PPI generalizability and - Does available PPI show that

heterogeneity preferences vary according to the
stage of disease severity, chronicity,
or other definable patient
characteristic? If so, how?
- Does available PPI include
preferences of patients across the
spectrum of the intended use
population? If no, specify the PPI
study population.
28

Availability of alternative - What other therapies are available for this
treatments or diagnostics condition?
- How effective are the alternative
treatments?
o How does their effectiveness
vary by subpopulation?
- How well-tolerated are the alternative
therapies?
o How does their tolerance vary by
subpopulation?
- What risks are presented by any available
Risk mitigation and indication - Could you identify ways to mitigate the
limiting risks (including limiting the indication
for use to a subset of the population in
which benefit outweighs risk
considerations) such as using product
labeling, establishing education
programs, providing add-on therapy,
etc?
- What is the type of risk
mitigation proposed?
29

Postmarket data - Are there other devices with similar
indications on the market? Are the
probabilities for effectiveness and rates of
harmful events from those devices similar
to what is expected for the device under
review?
- Is postmarket data available that changes
the risk/benefit evaluation from what was
available when the previous devices were
evaluated?
- Is there reason to consider evaluation of
any of the following elements further in
the postmarket setting due to the
risk/benefit evaluation as described
above?
o Longer-term device performance
o Effectiveness of training
programs or provider
preferences in use of device
o Sub-groups (e.g., pediatrics,
women)
o Rare adverse events
- Is there reason to expect a significant
difference between real world
performance of the device and the
performance found in premarket
experience with the device?
- Is there data that otherwise would be
provided to support approval that could
be deferred to the postmarket setting?
Novel technology addressing - How well is the medical need this device
unmet medical need addresses being met by currently
available therapies?
Summary of the Benefit(s) Summary of the Risk(s) Summary of Other Factors
30
Conclusions
Do the probable benefits outweigh the probable risks?
30
Appendix C
Worksheets for Hypothetical Examples
31
Worksheet for Hypothetical Example 1

- What primary endpoints or surrogate Reduction of symptoms.
Type of benefit(s)
endpoints were evaluated? Improved mobility.
- What key secondary endpoints or Longer life expectancy.
benefit?
- For each primary and secondary endpoint Substantial reduction of the patients
or surrogate endpoints evaluated: symptoms.
o What was the magnitude of each
treatment effect?
benefit?
scale?
- Was the study able to predict which There is 75% probability (predictive
patients will experience a benefit? probability) that a patient will experience
- What is the probability that a patient for the benefit once the device is on the
benefit(s)
whom the device is intended will market.
- How did the benefits evaluated vary The patients who experience the benefit
across sub-populations? (If the study was value it substantially. Patients also value
sufficiently powered for subpopulations, the opportunity to achieve the benefit.
these differences.)
- Could the duration, if relevant, of each Follow-up only to one year.
treatment effect, including primary and Patients with improved mobility tend to
secondary endpoints be determined? If have higher life expectancy.
so, what was it? Patients value the benefit, even if it were
- Is the duration of the benefit achieved of only for one year.
value to patients?
32


and consequences):
Device-related serious - What are the device-related serious Known risks associated with permanent,
adverse events adverse events for this product? implantable devices. Device fracture,
mechanical failure or adverse biological
response.
If necessary, it would be difficult to
remove the device.
Device-related non-serious - What are the device-related non-serious N/A

Procedure-related - What other procedure-related Surgery is non-routine and carries high

complications complications may a patient be subject risks.
to?
- What percent of the intended patient Low.
population would expect to experience a 1% chance of death from surgery
harmful event? Less than 3% chance of occurrence of a
- What is the incidence of each harmful harmful event after implantation.
event in the study population? Less than 3% chance of device fracture,
- How much uncertainty is in that estimate? mechanical failure, and adverse biological
- How does the incidence of harmful events response.
Duration of harmful events - How long does the harmful event last? The device-related adverse events last as
- Is the harmful event reversible? long as the device remains implanted, but
- What type of intervention is required to can be reversed by removing the device.
Risk from false-positive or - What are the consequences of a false N/A
negative?
diagnostic plan?
33

Uncertainty:
Quality of the study design - How robust were the data? Clinical study was well designed and
conducted, but the follow up was only 1
year.
Quality of the conduct of - How was the trial designed, conducted Questionable there were missing data.
the study and analyzed?
Robustness of the analysis - Are the study results repeatable? There were missing data, but sensitivity
of the study results - Is this study a first of a kind? analyses were conducted and the results
- Are there other studies that achieved are relatively robust.
similar results?
Generalizability of results - Can the results of the study be applied to The device is more appropriate for use by
the population generally, or are they more surgeons with specialized training.
intended for discrete, specific groups?
Patient-centric assessments and Do the device benefits and risks include This treatment is highly valued by patients
patient-reported outcomes effects on the health-related quality of life because they failed all other treatment
(PROs) or other patient-reported outcomes? options and the treatment may improve
their overall quality of life.
Characterization of the - How does the disease affect the patients Disease is very severe and affects patients
Disease that have it? quality of life and mobility. The disease is
- Is the condition treatable? chronic and incurable.
34
- Benefit and risk - What benefit(s) from this device Patients are willing to take the risk of
considerations of patient is (are) of most importance to getting the device implanted in
preference information patients? exchange for the opportunity to
- What risk(s) from this device is achieve the benefit because there are
(are) of most importance to no other treatment options and their
patients? symptoms are severe.
interventions?
willing to accept the probable risk(s) of
this device in exchange for the probable
benefit(s)?
- Does PPI demonstrate that most or all
of the patient population with the
PPI relevance and - Are the risks identifiable and definable?

comprehension - Do patients understand the type of
risk(s) and the likelihood of the risk(s)?
benefit(s)?

heterogeneity preferences vary according to the stage
of disease severity, chronicity, or other
definable patient characteristic? If so,
how?
- Does available PPI include preferences
of patients across the spectrum of the
intended use population? If no, specify
the PPI study population.
35

Availability of alternative - What other therapies are available for this There are alternatives available, but
treatments or diagnostics condition? patients receiving this device have
- How effective are the alternative already failed alternative treatments.
treatments?
therapies?
subpopulation?
Risk mitigation and indication - Could you identify ways to mitigate the Limit use to surgeons who have
limiting risks (including limiting the indication completed specialized training.
for use to a subset of the population in
which benefit outweighs risk
etc?
36

Postmarket data - Are there other devices with similar There are similar devices in the market
indications on the market? Are the for different indications and that enhances
probabilities for effectiveness and rates of the inference about long term adverse
harmful events from those devices similar event rates, such as device fractures.
to what is expected for the device under Longer term device performance, such as
review? duration of the benefit and long term
- Is postmarket data available that changes adverse event rates (beyond 1 year) could
the risk/benefit evaluation from what was be evaluated in the postmarket setting.
available when the previous devices were As long as the device is implanted by
evaluated? specially trained surgeons, as required in
- Is there reason to consider evaluation of the labeling, real world performance
any of the following elements further in should be similar to premarket
the postmarket setting due to the performance.
risk/benefit evaluation as described Effectiveness of training could be
above? assessed (and improved) as postmarket
o Longer-term device performance information becomes available.
women)
Novel technology addressing - How well is the medical need this device N/A

75% chance of improved patient Permanently implantable device that requires Patients are willing to tolerate the risks
mobility and quality of life. surgery. 25% chance that patient will because they have a high probability of
experience no benefit. Serious adverse events receiving a substantial benefit. Risks can
include death, device fracture, mechanical be mitigated by limiting to surgeons who
failure or an adverse biological response. have received specialized training.
37
Conclusions
Yes. There are no alternative treatments available for the intended population and the device treats a severe condition.
Patients have a 75% chance of experiencing a significant improvement in quality of life. Patients are willing to take the risk
even though it is uncertain that they will achieve the benefit, because if they benefit, the benefit is great. These patients
have failed alternative treatments, so they are not foregoing an effective treatment for an uncertain benefit. Finally, the
risks associated with this device, although serious, are not higher than those for similar treatments.
38

- What primary endpoints or surrogate Memory preservation.
Type of benefit(s)
endpoints were evaluated? Improvement of quality of life.
- What key secondary endpoints or Patients place an enormous value on the
surrogate endpoints were evaluated? benefit.
benefit?
- For each primary and secondary endpoint Large for patients in early stages of the
or surrogate endpoints evaluated: disease; smaller for patients in later stages
o What was the magnitude of each of the disease.
treatment effect?
benefit?
scale?
- Was the study able to predict which The trial was designed to study two
patients will experience a benefit? subgroups, subjects at early stages of the
- What is the probability that a patient for disease and subjects at late stages of the
benefit(s)
whom the device is intended will disease. It can be inferred that benefits
experience a benefit? will be higher for patients in early stages
- How did the benefits evaluated vary of the disease and lower for patients in
across sub-populations? (If the study was later stages of the disease.
these differences.)
- Could the duration, if relevant, of each Benefits should last as long as the device
treatment effect, including primary and remains implanted.
secondary endpoints be determined? If
so, what was it?
value to patients?
39


and consequences):
Device-related serious - What are the device-related serious Partial paralysis, loss of vision, loss of
adverse events adverse events for this product? motor skills, vertigo, and insomnia
Device-related non-serious - What are the device-related non-serious Personality shifts, mood swings, and
adverse events adverse events for this product? slurred speech
Procedure-related - What other procedure-related 8% risk of serious adverse events from

complications complications may a patient be subject surgery alone, even when done by highly
to? trained neurosurgeon.
- What percent of the intended patient High 8% risk of death from surgery; 1%
population would expect to experience a chance of a serious adverse event; and
harmful event? 5% chance of a non-serious adverse
- What is the incidence of each harmful event. When considered together, these
event in the study population? present a high risk.
- How does the incidence of harmful events Patients in the early stages of the disease
vary by subpopulation (if applicable)? will have higher risks due to longer
- Are patients willing to accept the permanence of the device. However,
probable risk of the harmful event, given those patients experience the higher
the probable benefits of the device? benefit.
Duration of harmful events - How long does the harmful event last? Permanent for death and serious adverse
- Is the harmful event reversible? events; possible reversal for non-serious
- What type of intervention is required to adverse events.
negative?
diagnostic plan?
40

Uncertainty:
Quality of the study design - How robust were the data? Good. The study was small, but the
confidence intervals for the endpoints
were reasonably narrow.
Quality of the conduct of - How was the trial designed, conducted Very good. Almost all subjects retuned
the study and analyzed? for the follow up visits.
Robustness of the analysis - Are the study results repeatable? Very robust. Subgroups for which the
of the study results - Is this study a first of a kind? device worked the best were identifiable
- Are there other studies that achieved from the results. A subgroup analysis
similar results? was pre-planned during the trial design.
Generalizability of results - Can the results of the study be applied to Generalizable because we know patients
the population generally, or are they more at an earlier stage of the disease respond
intended for discrete, specific groups? better.
Patient-centric assessments Do the device benefits and risks include This treatment is highly valued by
and patient-reported outcomes effects on the health-related quality of life patients because they have no other
(PROs) or other patient-reported outcomes? treatment options and it could
substantially improve their quality of
life.
Disease that have it? quality of life and memories. The disease
- Is the condition treatable? is chronic and incurable.
40
considerations of patient is (are) of most importance to getting the device implanted because
preference information patients? there are no other treatment options and
- What risk(s) from this device is their symptoms are extremely severe.
(are) of most importance to Patients with this kind of disease are
patients? often willing to risk death in order to
- Is there available qualitative or improve their prognosis.
interventions?
benefit(s)?

benefit(s)?

how?
41

Availability of alternative - What other therapies are available for this There are no alternative treatments
treatments or diagnostics condition? available.
treatments?
therapies?
subpopulation?
Risk mitigation and indication - Could you identify ways to mitigate the Provide training for surgeons.
limiting risks (including limiting the indication Note in the labeling that this device is
for use to a subset of the population in most effective for patients in the early
which benefit outweighs risk stages of the disease.
etc?
42

Postmarket data - Are there other devices with similar The device is first-of-a-kind and there
indications on the market? Are the are no similar devices on the market. As
probabilities for effectiveness and rates of a consequence, there is no prior
harmful events from those devices similar information on other devices that could
to what is expected for the device under be used for inferences on the performance
review? of this device. Therefore, longer term
- Is postmarket data available that changes performance, including maintenance of
the risk/benefit evaluation from what was effectiveness, long term adverse events,
available when the previous devices were and device duration, should be assessed
evaluated? in the postmarket setting.
any of the following elements further in A postmarket study will probably be
the postmarket setting due to the recommended.
above?
women)
Novel technology addressing - How well is the medical need this device Breakthrough technology. It is expected
unmet medical need addresses being met by currently that future improvements will reduce the
available therapies? risks associated with the current version
of the device.
High chance of benefit for Permanently implantable device that requires Patients are willing to tolerate the risks
patients in the early stages of the surgery. 8% risk of death from surgery; 1% risk because they receive a substantial benefit
disease. Benefits include of serious adverse events; 5% risk of non- if the device works and there are no
improved memory and quality of serious adverse events. For younger patients, alternative treatments available. Risks
life. Benefits are extremely the risk is higher because they will live with the can be mitigated by providing training
valued by patients and their device for a longer period of time. and limitations in the labeling.
families.
43
Conclusions
Yes. The benefits outweigh the risks for some patients and FDA would like to provide the opportunity for those patients
who would like to take the risk to obtain the benefit. There are no alternative treatments available, the device treats a
severe condition, and patients experience a significant improvement in quality of life and memory. Patients are willing to
take the risk even though there is a high risk of death because the benefits that they receive are so significant and life-
changing. The risks associated with this device are high; however, they can be mitigated through training and limitations
in the labeling. Also, this treatment is novel and there are no other similar alternatives on the market. Therefore, even
though the risks are high, due to the substantial benefit achieved and the mitigations available, the benefits outweigh the
risks in this case. Finally, it is expected that the technology and surgical technique will improve with further iterations and
the adverse event rates will decrease.
44

- What primary endpoints or surrogate Avoidance of morbidity from breast
Type of benefit(s)
endpoints were evaluated? biopsy procedures.
- What key secondary endpoints or
benefit?
- For each primary and secondary endpoint Avoiding inconvenience, pain and
or surrogate endpoints evaluated: complications associated with breast
o What was the magnitude of each biopsy procedure.
treatment effect?
benefit?
scale?
- Was the study able to predict which Approximately 57% (228/400), for the
patients will experience a benefit? intended use population.
- What is the probability that a patient for
benefit(s)
whom the device is intended will
these differences.)
- Could the duration, if relevant, of each Variable. Might be long term (no biopsy
treatment effect, including primary and needed, lifelong), or might last only until
secondary endpoints be determined? If follow-up exam prompts a biopsy.
so, what was it?
value to patients?
45


and consequences):
Device-related serious - What are the device-related serious Some patients with biopsy-detectible
adverse events adverse events for this product? breast cancer will not have the cancer
detected/treated until follow-up exam
(assuming that follow-up exam occurs).
Device-related non-serious - What are the device-related non-serious Failure to characterize non-malignant
adverse events adverse events for this product? disease that would have been revealed by
biopsy.
Procedure-related - What other procedure-related N/A

to?
- What percent of the intended patient For the most serious harmful events,
population would expect to experience a approximately 1% (3/400) in the intended
harmful event? use population. Slightly more than 1%
- What is the incidence of each harmful (3/228) among test-negative subjects.
Duration of harmful events - How long does the harmful event last? May be lifelong, if treatable/curable
- Is the harmful event reversible? breast cancer is not detected.
Risk from false-positive or - What are the consequences of a false See above.
negative?
diagnostic plan?
46

Uncertainty:
Quality of the study design - How robust were the data? There is no assurance that the clinical
impact of breast cancers missed among
patients with BI-RADS 4 mammography
results is equivalent to the clinical impact
of breast cancers among patients who
have BI-RADS 3 results. Hence, there is
uncertainty about the extent of the
probable risk(s)/harm(s).
Quality of the conduct of - How was the trial designed, conducted Good.
Robustness of the analysis - Are the study results repeatable? Reasonably robust.
of the study results - Is this study a first of a kind?
- Are there other studies that achieved
similar results?
Generalizability of results - Can the results of the study be applied to The relative value that patients place on
the population generally, or are they more avoiding biopsy morbidity, compared to
intended for discrete, specific groups? the clinical impact of missing a biopsy-
detectible cancer, is not known.
Patient-centric assessments Do the device benefits and risks include Patients weigh differently the value of
and patient-reported outcomes effects on the health-related quality of life the benefits and the risks. Information
(PROs) or other patient-reported outcomes? about patients who elect not to have
biopsies after receiving a BI-RADS 3
result might be helpful.
Disease that have it? quality of life. The disease is chronic, may
- Is the condition treatable? be incurable and, in some cases, fatal.
47
- Benefit and risk - What benefit(s) from this device Patients tolerance for delayed diagnosis
considerations of patient is (are) of most importance to and treatment of breast cancer typically is
preference information patients? low. This needs to be weighed against the
- What risk(s) from this device is value that patients place on avoiding
(are) of most importance to biopsy-related morbidity.
patients?
interventions?
benefit(s)?
benefit(s)?

how?
48

Patient-Centric Assessment - What benefit(s) from this device is (are) of Patients weigh differently the value of the
most importance to patients? benefits and the risks. Information about
o Do the device benefits include patients who elect not to have biopsies
effects on the health-related after receiving a BI-RADS 3 result might
quality of life or other patient- be helpful.
reported outcomes (PROs)?
- What risk(s) from this device is (are) of
most importance to patients?
o Do the device risks include
effects on the health-related
quality of life or other patient-
reported outcomes (PROs)?
- Do any of these issues vary according to
disease severity, chronicity or other
definable patient characteristic?
Availability of alternative - What other therapies are available for this None, for the proposed intended use.
treatments or diagnostics condition?
treatments?
therapies?
subpopulation?
Risk mitigation and indication - Could you identify ways to mitigate the Follow-up evaluation of patients might
limiting risks (including limiting the indication limit harms caused by erroneous test
for use to a subset of the population in results. A plan is needed to handle
which benefit outweighs risk circumstances with serially BI-RADS 4
considerations) such as using product mammograms and negative test results.
etc?
49

Postmarket data - Are there other devices with similar If it is determined that the device is
indications on the market? Are the approvable, then additional (postmarket)
probabilities for effectiveness and rates of information that refines the understanding
harmful events from those devices similar of the uncertainties and patient tolerance
to what is expected for the device under for risk and perspective on benefit might
review? be in order.
evaluated?
above?
women)
Novel technology addressing - How well is the medical need this device The technology is not novel.

The benefit in this case is to Approximately 1% of tested patients (slightly In current practice, approximately 2% of
avoid biopsy-related morbidity more than 1% of test-negative patients) will patients with abnormal (i.e., BI-RADS 3)
in a substantial fraction of BI- have delay in detection/treatment of breast mammography results have breast cancer
RADS 4 patients. cancer. that (because of deferred biopsy) might
not be detected until follow-up exam.
50
Conclusions
The kinds and probabilities of benefit and risk are reasonably defined. A clinical practice reference for acceptable risk is
put forth, and the tests performance characteristics are aligned with that clinical practice reference. Weighting of the
different kinds of benefit versus risk is not directly addressed. Additional information is needed to establish the overall
acceptability of trade-offs between the different kinds of benefit and risk. Given that the benefits are uncertain and the
downside risk (for a very small number of patients) could be substantial, this device could be not approvable, but FDA
would be likely to take it to panel prior to making a decision.
51

- What primary endpoints or surrogate Support the stability of the primary
Type of benefit(s)
endpoints were evaluated? device (movement prevention) and
- What key secondary endpoints or reduction in primary device
surrogate endpoints were evaluated? complications.
benefit?
- For each primary and secondary endpoint A very high probability (almost 100%) of
or surrogate endpoints evaluated: reduction of primary device migration
o What was the magnitude of each and substantial reduction of primary
treatment effect? device complications.
benefit?
scale?
- Was the study able to predict which A very high probability (almost 100%) of
patients will experience a benefit? prevention of migration.
- What is the probability that a patient for A very high probability (almost 100%) of
benefit(s)
whom the device is intended will prevention of complications.
these differences.)
- Could the duration, if relevant, of each Data up to one year of follow-up.
treatment effect, including primary and However, the benefit is expected to last
secondary endpoints be determined? If for as long as the device remains
so, what was it? implanted.
value to patients?
50


and consequences):
Device-related serious - What are the device-related serious None.

Device-related non-serious - What are the device-related non-serious Complications related to movement.
Procedure-related - What other procedure-related None.

to?
- What percent of the intended patient Very low.
population would expect to experience a
harmful event?
- What is the incidence of each harmful
Duration of harmful events - How long does the harmful event last? Harmful events are reversible.
- Is the harmful event reversible?
negative?
diagnostic plan?
51

Uncertainty:
Quality of the study design - How robust were the data? The trial was designed to study an
investigational system that included this
device. The level of data collected was
very good for a Class II device.
Quality of the conduct of - How was the trial designed, conducted Very good.
Robustness of the analysis - Are the study results repeatable? The results are robust for up to one year
of the study results - Is this study a first of a kind? of follow-up. Subjects will receive
- Are there other studies that achieved continual follow-up through five years,
similar results? but only the one year data were required
to evaluate the device.
Generalizability of results - Can the results of the study be applied to The device has been evaluated for use
the population generally, or are they more with all commercially-available primary
intended for discrete, specific groups? devices in the U.S. Use with other
devices used only outside the U.S. has not
been evaluated.
Patient-centric assessments Do the device benefits and risks include This treatment is highly valued by
and patient-reported outcomes effects on the health-related quality of life patients because it provides for a
(PROs) or other patient-reported outcomes? minimally-invasive solution to a problem
that would otherwise have to be
addressed by surgery, and the clinical trial
results show that the device works, even if
the follow-up is only one year in duration.
Characterization of the - How does the disease affect the patients The disease is severe.
Disease that have it?
- Is the condition treatable? The disease is chronic and treatable with
- How does the condition progress? either open surgery or minimally-invasive
device placement. This device offers an
additional method of improved treatment
for those who use the minimally-invasive
procedure.
52
considerations of patient is (are) of most importance to getting the device implanted because they
preference information patients? are already undergoing or have undergone
- What risk(s) from this device is surgery and the device has an excellent
(are) of most importance to record of preventing migration and
patients? complications, which can be present
without the use of the device.
interventions?
benefit(s)?
benefit(s)?

how?
53

Availability of alternative - What other therapies are available for this There are no alternative minimally-
treatments or diagnostics condition? invasive treatments available to provide
- How effective are the alternative support for a primary device that could
treatments? migrate or present complications. This
o How does their effectiveness device is first-of-a-kind.
therapies?
subpopulation?
Risk mitigation and indication - Could you identify ways to mitigate the Special controls, which include
limiting risks (including limiting the indication demonstration of biocompatibility,
for use to a subset of the population in sterility, safety and effectiveness
which benefit outweighs risk (including durability, compatibility,
considerations) such as using product migration, resistance, corrosion
labeling, establishing education resistance, and delivery and deployment);
programs, providing add-on therapy, evaluation of the MR-compatibility of the
etc? device; validation of electromagnetic
- What is the type of risk compatibility of device; limiting of the
mitigation proposed? device to prescription use; and clear
instructions in the labeling regarding the
safe and effective use of the device.
54

Postmarket data - Are there other devices with similar Patients were followed for one year
indications on the market? Are the during the clinical trial. Long term
probabilities for effectiveness and rates of performance of the device may be
harmful events from those devices similar assessed in the postmarket setting.
to what is expected for the device under
review?
evaluated?
above?
women)
Novel technology addressing - How well is the medical need this device This is a first-of-a-kind device.

Highly probable improvement in Permanently implantable device that requires Patients are willing to tolerate the risks
treatment of failed or failing minimally-invasive surgery. Serious adverse because they receive a substantial benefit.
underlying device. How events include death, device fracture, mechanical
treatment will affect patient failure or an adverse biological response.
outcomes is highly variable on
other cofactors.
55
Conclusions
Yes. The device provides substantial benefits and low risks. Moreover, given the ability to mitigate risks through special
controls and the fact that this device is not life-supporting or life-sustaining, FDA would be likely to grant a de novo request
to classify this device into Class II. For lower-risk devices, less evidence may be necessary to tip the benefit-risk balance in
favor of approval. In this case, even though the follow-up data are only one year in duration, the moderate-risk nature of
the device, its non-invasive application method and the fact that the risks can be mitigated through special controls could
lead to a de novo classification under Class II.
56

1772

Caricato da

Informazioni sul documento

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

1772

Caricato da

Copyright:

Formati disponibili

Guidance for Industry and Food

and Drug Administration Staff

Factors to Consider When Making

The draft of this document was issued on August 15, 2011.

As of October 23, 2016, this document supersedes

U.S. Department of Health and Human Services

Center for Devices and Radiological Health

Center for Biologics Evaluation and Research

4. Factors FDA Considers in Making Benefit-Risk Determinations......................................................................8

5. Examples of Benefit-Risk Determinations.......................................................................................................14

Guidance for Industry and

Factors to Consider When Making

approval (PMA) applications or de novo classification requests. This guidance applies to

3.2 Types of Scientific Evidence

cell-based studies, and computer simulations. These tests characterize mechanical,

Although a great deal of emphasis is placed on the importance of clinical data in

3.3 Benefit-Risk Determinations

4. Factors FDA Considers in Making Benefit-Risk

4.1 Assessment of the Benefits of Devices

Extent of the probable benefit(s): FDA assesses information provided in a PMA

- The magnitude of the benefit(s) we often assess benefit along a scale or

- The probability of the patient experiencing one or more benefit(s) based on

4.2 Assessment of the Risks of Devices

o Device-related non-serious adverse events those events that may have

- Probability of a harmful event the proportion of the intended population that

- Risk from false-positive or false-negative results for diagnostics if a

4.3 Additional Factors in the Assessment of the Probable Benefits and

Uncertainty there is never 100% certainty when determining reasonable assurance of

Patient-centric assessments and patient-reported outcomes (PROs) We

Characterization of the disease the treated or diagnosed condition, its clinical

- Severity of disease or condition patients suffering from very severe diseases

- Availability of alternative treatment/diagnostic options (also see below) if

Availability of alternative treatments or diagnostics when making benefit-risk

5. Examples of Benefit-Risk Determinations

5.1 Hypothetical Examples

The results of the pivotal clinical trial revealed the following:

Approval/Non-Approval Considerations: The probability that a patient will experience

A novel device that replaces a patients memory is developed to treat Alzheimers

NovelTechnologyAddressingUnmetMedicalNeed: There is no other similar technology

Approval/Non-Approval Considerations: The device will confer a substantial benefit

Positive test result (High Risk): immediate biopsy is recommended.

Test-negative BI-RADS 4 patients, who do not undergo biopsy, will receive no

Availability of alternative treatments or diagnostics: There are no other in vitro

Approval/Non-Approval Considerations: The kinds and probabilities of benefits and

primary device as compared to when it is implanted without the benefit of enhanced

The results of the pivotal clinical trial revealed the following:

this device, FDA required demonstration of biocompatibility, sterility, safety and

NovelTechnologyAddressingUnmetMedicalNeed: This device is the first system that

Approval/Non-Approval Considerations: The clinical trial results provide assurance of

5.2 Examples Based on Actual FDA Benefit-Risk Determinations

Intersection of this Guidance with ISO 14971

Worksheet for Benefit-Risk Determinations

Factor Questions to Consider Notes

- For each primary and secondary endpoint

Factor Questions to Consider Notes

Severity, types, number and

Device-related serious - What are the device-related serious

Device-related non-serious - What are the device-related non-serious

Procedure-related - What other procedure-related

Factor Questions to Consider Notes

Quality of the study design - How robust were the data?

Quality of the conduct of the - How was the trial designed,

Robustness of the analysis of - Are the study results repeatable?

Generalizability of results - Can the results of the study be applied to